Kosmas Macha, Bastian Volbers, Bernd Kallmünzer
Direct Oral Anticoagulants (DOAC) are highly effective for the prevention of systemic embolism and ischemic stroke in non-valvular atrial fibrillation, but the optimal time point of treatment initiation after stroke has not been defined yet. The very early period after stroke bears a particular high risk of stroke recurrence and the timely initiation of secondary prevention at that early stage could therefore be most beneficial for the patient. Contrarily the use of DOAC in the hyperacute phase of stroke might increase the risk of bleeding complications. The prospective trials investigating the use of DOAC versus vitamin K antagonists did not include patients during the first weeks after stroke due to safety concerns. However, preliminary results from smaller cohorts suggest that the use of DOACs in this early time frame is feasible and safe. Larger prospective trials are warranted to confirm these results and investigate the efficacy of early treatment initiation.DOI: 10.29245/2572.942X/2017/3.1112 View / Download Pdf
Ricardo Vieira Botelho1, Juliete Melo Diniz1
Background: Adult craniocervical junction malformations have been described as Chiari malformation (CM) and Basilar invagination (BI). Recently, angular craniometric studies have identified differences among subtypes of malformations and reveled new relationships between skull and spine.
Objective: The scope of this study is to summarize the knowledge related to craniometric relationship in pathophysiology of these diseases.
Results: In CM, angular craniometric measures are not different from normal controls. In BI type I and II there is an increased craniocervical Kyphosis associated to cervical spine lordosis. Chamberlain’s line violation evaluation reveals that there is a downward angulation of the skull towards the upper cervical spine in BI.
Conclusion: BI should be considered a craniometrical kyphosis rather than a prolapse of the cervical spine to the skull base.DOI: 10.29245/2572.942X/2017/3.1110 View / Download Pdf
Ai-Ling Li1,2,3*, Yuan Bo Peng11Department of Psychology, The University of Texas at Arlington, 501 South Nedderman Drive, Arlington, Texas 76019, USA
2Department of Psychological & Brain Sciences, Indiana University Bloomington, 1101 E. 10th St., Bloomington, IN 47405, USA.
3Gill Center for Biomolecular Science, Indianan University Bloomington, 702 N. Walnut Grove Ave., Bloomington, IN 47405, USA.
Pain and depression are two major health issues that we are currently facing. Chronic pain is the main reason that people seek medical care; and numerous people commit suicide each year because of depression. These two pathological conditions often coexist. Chronic pain patients are more likely to develop major depressive symptoms, while depressed patients reported more pain symptoms than normal healthy population. Understanding the common mechanisms associated with depression and pain is important for developing the effective strategy to treat this comorbidity. In this review, the potential mechanisms that contribute to both depression and pain are discussed from four perspectives, the morphological changes in the brain, monoamine deficiency, brain-derived neurotrophic factor (BDNF) reduction in the hippocampus, and the hypothalamic-pituitary-adrenocortical (HPA) axis dysfunction.DOI: 10.29245/2572.942X/2017/3.1116 View / Download Pdf
Kolja Schürmann and Arno Reich
In-hospital stroke (IHS), which represents between 2.2% and 17% of all strokes, differs from community-onset stroke (COS) in etiology, treatment approaches and outcome. Patients hospitalized for cardiac disease are especially vulnerable to predominantly cardioembolic IHS. Stroke severity, functional outcome and mortality compare unfavorably to COS. Difficulties in symptom recognition, intra-hospital delays, various stroke mimics, critical underlying diseases and contraindications against standard systemic thrombolysis represent difficulties in IHS treatment. Quality of care may be improved by educating medical staff, implementing a code stroke and a CT-rendezvous system, providing access to specialized care (e.g. on stroke units) and endovascular reperfusion therapy as well as neuromonitoring, where applicable.DOI: 10.29245/2572.942X/2017/2.1114 View / Download Pdf
Bruno Fattori1, Gabriele Siciliano2, Amelia Santoro1, Salvatore Osvaldo Romeo1, Andrea Nacci1
Our purpose was to assess the relationship between the disease severity of Amyotrophic Lateral Sclerosis (ALS) and the main parameters of Fiberoptic Endoscopic Evaluation of Swallowing (FEES), indirectly hypothesizing for FEES a role as clinical indicator of the progression of ALS. We studied 220 patients (101 women, 119 men) with ALS; of these, 148 had spinal and 72 bulbar onset. They were analyzed according to the Amyotrophic Lateral Sclerosis Functioning Rating Scale (ALSFRS) and the b-ALSFRS subscale (bulbar scale). All subjects underwent FEES. Post-swallowing residue was classified into four classes (0-3); premature spillage and aspiration were considered either present or absent. An in-depth statistical analysis revealed a highly significant relationship between the FEES parameters studied and the severity of the disease assessed through ALSFRS and b-ALSFRS (p < 0.0001), no matter what bolus texture was used. Moreover, statistical analysis showed a highly significant association between the classes of severity in bulbar forms and all the FEES parameters, no matter what type of bolus was administered (p <0.0001), whereas a significant correlation in spinal forms only for post-swallowing residue with solid (p= 0.025) and semisolid (p= 0.034) boluses. FEES is a good indicator of the severity of dysphagia and of its progression in patients with ALS, as well as of the clinical progression of the disease.DOI: 10.29245/2572.942X/2017/2.1113 View / Download Pdf
Sean P. Didion, PhD1
Nitric oxide derived from endothelial nitric oxide synthase (eNOS) has been shown to be a major mediator of endothelium-dependent responses in cerebral blood vessels. Loss of a single eNOS gene is not associated with any apparent negative consequences on endothelial function in most blood vessels. In contrast, we have recently demonstrated that heterozygous eNOS gene deficiency in combination with a high fat diet is associated with marked impairment of endothelial function. These findings provide an important example of eNOS haploinsufficiency and one that directly impacts the cerebral vasculature. A major mechanism associated with the impairment of endothelial function with eNOS deficiency and a high fat diet appears to be related to increases in plasma IL-6 that serves to further reduce the bioavailability of NO either directly or indirectly via reductions in eNOS expression or activity and via increases in vascular superoxide. Taken together, these findings provide important insights into genetic and molecular mechanisms that promote endothelial dysfunction in response to a high fat diet in cerebral blood vessels with inherent reductions in eNOS gene expression, such as those due to eNOS gene polymorphisms. These findings also highlight the importance of eNOS mice to study the effects of eNOS haploinsufficiency on cerebral blood vessels.DOI: 10.29245/2572.942X/2017/2.1111 View / Download Pdf
Deepika Rajesh, H. Ian Robins* and Steven. P. Howard
The prognosis for patients with high-grade glioma remains dismal illustrating the need for the development of chemotherapeutic strategies intended to synergize with treatment modalities of proven efficacy such as radiation therapy. Karenitecin, (BNP1350,7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin), is a semisynthetic, orally administrable camptothecin, with physiochemical properties favoring increased accumulation of active drug within the central nervous system. This study was initiated to determine whether Karenitecin could potentiate radiosensitivity in T98G and MO59K glioma cell lines. Using clinically relevant doses of each agent, it was demonstrated that Karenitecin pretreatment significantly enhances radiosensitivity and was shown to be synergistic by isobolographic analysis. Karenitecin treatment resulted in a transient arrest in the G2/M phase of the cell cycle with an associated increase in expression of cyclin B1. It was further demonstrated that Karenitecin treatment results in activation of caspases, generation of reactive oxygen species, collapse of the mitochondrial membrane potential and inhibition of total protein kinase C, all of which could enhance radiosensitivity. These in vitro data suggest that Karenitecin has potential as a radiosensitizer in the treatment of malignant glioma.DOI: 10.29245/2572.942X/2017/2.1109 View / Download Pdf
Joel Ramireza-b, Melissa F. Holmesa, Fuqiang Gaoa-b, and Sandra E. Blacka-c
With dementia prevalence on the rise, it is imperative to develop novel therapies and treatments to address the increasing recognition of the clinical and pathological overlap of Alzheimer’s and cerebrovascular disease - the top two leading causes of dementia. Although the research methods currently employed have made great advances towards our understanding of comorbid neurovascular and neurodegenerative diseases, these knowledge-based silos have had a tendency to operate in relative isolation. As our cumulative body of knowledge within each platform increases, so should the coordination of research. By examining current findings in neuroimaging, neuropsychology, genetics, neuropathology, and molecular neurobiology, this blanket-level mini-review will examine the spectrum of research findings that contributes to our understanding of Alzheimer’s and vascular contributions to dementia.DOI: 10.29245/2572.942X/2017/1.1105 View / Download Pdf
Ricardo de Oliveira-Souza
The chief goal of the present review is to present clinicoanatomic evidence that, (i) in contrast to most vertebrates, spastic hemiplegia in man is a symptom of damage to the pyramidal tracts, and (ii) although extrapyramidal structures are often injured as a contingency of anatomical proximity in cases of pyramidal damage, the extrapyramidal system plays no role in the production of human spastic hemiplegia. The views herein discussed reconcile several apparent incongruences concerning the pathophysiology of the human pyramidal syndrome. From a neurobiological perspective, the progressive commitment to occasional, habitual and obligate bipedalism fostered a profound internal reorganization of the mammalian brain at the early stages of human phylogenesis. The major anatomical counterpart of this reorganization was an unprecedented increase of the ansa lenticularis fiber system, which ultimately redirected the product of subcortical motor activity up to the motor cortices from which the pyramidal tracts originate. In this sense, while the fundamental motor organization of vertebrates is represented by the extrapyramidal system, the dominant motor plan in humans is uniquely represented by the prepyramidal system.DOI: 10.29245/2572.942X/2017/2.1100 View / Download Pdf
Angela Trovato1, Manuela Pennisi1,5, Rosalia Crupi2*, Rosanna Di Paola2, Alice Alario1, Sergio Modafferi1, Gabriele Di Rosa1, Tito Fernandes3, Anna Signorile4, Luigi Maiolino6, Salvatore Cuzzocrea2 and Vittorio Calabrese1**
Abnormal redox homeostasis and oxidative stress have been proposed to play a role in the etiology of several neuropsychiatric disorders and emerging interest has recently focused on markers of oxidative stress and neuroinflammation in neurodegenerative disorders as well as in different forms of chronic mental illness. Oxidative stress and altered antioxidant systems have been considered an important factor underlying the pathogenesis of Alzheimer’s disease (AD). Altered expression of genes related to oxidative stress, oxidative damage to DNA, protein and lipids, as well as alterations in the redox state in central and peripheral tissues could act synergistically, and contribute to the course of the disease. Specifically, we discuss the emerging role of lipoxinA4 and inflammasome in neurodegeneration. However, the notion that low levels of stress can induce responses that may be protective against the pathogenic processes is a frontier area of neurobiological research focal to understanding and developing therapeutic approaches to neurodegenerative disorders. Herein, we discuss the potenial therapeutic role of Coriolus versicolor, a mushrooom, well known in China as Yun Zhi. We propose a potentially innovative treatment for AD and, possibly, other neurodegenerative conditions associated to neuroinflammation.DOI: 10.29245/2572.942X/2017/2.942X/2017/1.1088 View / Download Pdf
Morgan Sturgeon1, Perry Wu2, and Robert Cornell1,2*1Molecular and Cell Biology Graduate Program, University of Iowa, Iowa City, Iowa
2Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa
Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system with a clinically heterogeneous presentation that includes progressive loss of dopaminergic (DA) neurons in the substantia nigra. A minority of PD cases are familial and are caused by mutations in single genes. Most cases, however, are idiopathic PD, a complex multifactorial disorder with environmental and genetic contributors to etiology. Here, we first briefly summarize published evidence that among environmental contributors is dietary deficiency of magnesium. We then review genetic data suggesting that mutations in genes encoding two proteins contributing to cellular magnesium homeostasis confer risk for PD or other Parkinsonian conditions. First, the gene encoding magnesium transporter SLC41A1 is, among others, a candidate for the causative gene in the PARK16 locus where variation is associated with risk for idiopathic Parkinsonian disease. Studies of the function of SLC41A1 in animal models are needed to test whether this protein has a role in maintenance of dopaminergic neurons. Second, in a small study, a hypomorphic variant of TRPM7, a magnesium-permeable channel, was over-represented in cases of amyotrophic lateral sclerosis/ Parkinson dementia complex versus controls from the same ethnic group. Although this association was not detected in a second study, in zebrafish Trpm7 is necessary for terminal differentiation and reduction of toxin-sensitivity in dopaminergic neurons. Overall, epidemiological results support the possibility that mutations in genes relevant to magnesium homeostasis would alter PD risk, but deeper genetic analyses of PD patients are necessary to confirm whether SLC41A1 and TRPM7 are among such genes.DOI: 10.29245/2572.942X/2016/9.1102 View / Download Pdf
Arnauld Belmer1*, Vanessa Lanoue3, Omkar L. Patkar1, and Selena E. Bartlett1,21Translational Research Institute, Queensland University of Technology (QUT), Brisbane, Australia
2Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology (QUT), Brisbane, Australia
3Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Australia
Serotonin neurons originate from the brainstem raphe nuclei and innervate the entire brain to regulate mood, emotion, sleep, appetite and aggression. Previous electron microscopy (EM) studies have revealed that 5-HT boutons directly contact several neuronal populations via asymmetrical (excitatory) or symmetrical (inhibitory) synapses. Additionally, 5-HT boutons sometimes form “triads” with the pre and postsynaptic components of asymmetrical or symmetrical synapses to modulate their activity. However, the exact proportion and distribution of 5-HT excitatory/inhibitory synapses and triads within the entire brain remains poorly described. Recently, we have published a novel semi-quantitative approach which combines fluorescent confocal microscopy and 3D reconstruction of 5-HT fibers apposed to excitatory and inhibitory neurochemical synapses (triads). Here, we review the similarities and differences in the distribution of 5-HT asymmetrical/symmetrical synapses observed in EM and the distribution of 5-HT excitatory/inhibitory triads quantified in our recent study. We further put into perspective the possible physiological role played by 5-HT triads in the regulation of glutamate and GABA signaling in these various brain regions.DOI: 10.29245/2572.942X/2016/9.1079 View / Download Pdf
A.H. Rajput*, MBBS, FRCPC; A. Rajput, MD, FRCPC
Saskatchewan Movement Disorders Program, University of Saskatchewan/ Saskatoon Health Region
Parkinsonism in both spouses has been reported in only 20 couples in the literature so far. Six of the studies included only one or two couples, but one study reported nine couples. Fifteen of the couples reported by others consisted of only clinical data. By contrast, our study of five couples had detailed clinical, pathological and genetic observation on all ten individuals. We found no evidence of person-to-person transmission of parkinsonism. Details of that study are provided in this review.
The literature evidence to date indicates that neither Parkinson’s disease nor other common parkinson variants – multiple system atrophy or progressive supranuclear palsy are transmitted by sexual or close personal contact in the married couples. As well, these syndromes are not based on shared environments or same genetic mutation.
The best explanation for parkinsonism in both partners of non-consanguineous couples is, that Parkinson syndrome in each spouse is a coincidental disorderDOI: 10.29245/2572.942X/2016/9.1089 View / Download Pdf
Sonja Sucic, Ameya Kasture, H. M. Mazhar Asjad, Carina Kern, Ali El-Kasaby and Michael Freissmuth*Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria
The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue in vitro and in vivo. As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation.DOI: 10.29245/2572.942X/2016/9.1098 View / Download Pdf
Mélanie H. Thomas1, Sandra Pelleieux1,2, Nicolas Vitale3, Jean Luc Olivier1,2*
Alzheimer’s disease is a very complex disease in which neuroinflammation and synaptic dysfunctions play a critical role in association with the two well-known molecular agents of the disease, the Aβ peptide oligomers and the hyperphosphorylated tau protein. Arachidonic acid, the main member of the ω-6 series, is quantitatively the second polyunsaturated fatty acid in brain and is mainly esterified in membrane phospholipids. It is specifically released by the cytosolic phospholipase A whose inhibition or gene suppression counteract the deleterious effects of Aβ peptide oligomers on cognitive abilities. Arachidonic acid can be reincorporated under the action of the acyl-CoA synthetase 4 and lysophospholipid acyltransferases which remain to be characterized. Free arachidonic acid can be involved in Alzheimer’s disease through several mechanisms. First it is converted by cyclooxygenases-1/2 and the specific prostaglandin synthases into PGE2 and PGD2 which contributes to the occurrence and progression of neuroinflammation. Neuroinflammation has positive as well as negative effects, by favoring Aβ peptide clearance on one hand and by increasing the production of neurotoxic compounds on the other hand. Second, free arachidonic acid is also involved in synaptic functions as a retrograde messenger and as a regulator of neuromediator exocytosis. Third, some studies indicated that free arachidonic acid and its derivatives activate kinases involved in tau hyperphosphorylation. In addition, the dietary intakes of arachidonic acid in western food increased in the last period. Taken together, these various reports support the hypothesis that arachidonic acid is interesting target in nutrition-based preventive strategies against this disease.DOI: 10.29245/2572.942X/2016/9.1086 View / Download Pdf
Ahmed Hasanin1*, Dina Zakaria1, Ahmed Allam2
Neurogenic stress cardiomyopathy (NSC) is a stress induced cardiomyopathy reported in various neurological disorders. The most widely accepted theory for the mechanism of NSC is the “catecholamine hypothesis”. The available evidence suggests the presence of NSC in patients with severe TBI. The presence of cardiac injury could be a poor prognostic finding in patients with TBI. The possible cardiac injury in TBI patients would make the critical care physicians more cautious with hemodynamic management of these patients. Larger studies with more sophisticated asessment would help to confirm the presence of cardiac injury in these patients.DOI: 10.29245/2572.942X/2016/8.1090 View / Download Pdf
Gordon J. Horn1* & Frank D. Lewis21Florida State University, College of Medicine, USA
2Medical College of Georgia at Augusta University, USA
The purpose of this research was to evaluate the effectiveness of post-hospital neurobehavioral intensive (NBI) programs for treating acquired brain injury survivors with significant symptoms of behavioral dyscontrol and to identify variables that predict functional outcome. Subjects were 219 adults with acquired brain injury (predominately traumatic brain injury, 81%) exhibiting moderate to severe irritability, agitation, and/or aggression (includes verbal or physical) that were discharged from six NBI programs across five states. Prior to treatment, all participants demonstrated neurobehavioral impairment preventing the individuals from living in the community. All participants were assessed using the Mayo-Portland Adaptability Inventory – 4 at admission and discharge from program. A Repeated Measures MANOVA revealed significant improvement on the three MPAI-4 subscales at time of discharge. With control for participant age, a hierarchical multiple regression analysis revealed three significant MPAI-4 predictors of outcome: initiation, impaired awareness, and fund of information. Findings demonstrated that significant functional improvement can be realized with extremely chronic behaviorally intensive brain injured adults. Treatment effects may be enhanced by early intervention focused on appropriate response initiation/ inhibition, self-awareness of behavior on others, and information integration to facilitate appropriate response formation.DOI: 10.29245/2572.942X/2016/8.1078 View / Download Pdf
Miguel L. Concha1,2,3*, Patricio Ahumada-Galleguillos1,2
The habenula (Hb) of vertebrates is a dorsal and bilateral diencephalic nuclear complex that works as an anatomical hub integrating cognitive, emotional and sensory networks to regulate mood, motivation and value-based decision-making, among other functions. Across vertebrates, the Hb organises into two conserved separate components (medial and lateral in mammals equivalent to dorsal and ventral in more basal vertebrate species), which are thought to subserve different functions based on a partial independence of their connectivity systems. As a complex, the Hb shows morphological, molecular and connectivity differences between the left and right sides in a wide range of vertebrate species, which in some cases extend to the functional and behavioural levels. Habenular asymmetries are particularly prominent in basal vertebrate species but become less evident in amniotes and particular mammals. In humans, recent evidence reveals that, under an overall symmetry morphology, the Hb shows lateral differences in volume, activation, metabolism and susceptibility to damage that suggest an asymmetric condition of this nuclear complex. Here, we review the evidence supporting this view and discuss the possible origin of this asymmetric trait in humans from an evolutionary developmental perspective.DOI: 10.29245/2572.942X/2016/8.1094 View / Download Pdf
Faith C. Robertson B.S.,1,2 Hormuzdiyar H. Dasenbrock M.D., M.P.H.,1,2,3 William B. Gormley M.D., M.P.H., M.B.A.1,2,3
Malignant cerebral edema is a potential consequence of large territory cerebral infarction, as the resultant elevation in intracranial pressure may progress to transtentorial herniation, brainstem compression, and death. In appropriate patients, decompressive hemicraniectomy (DHC) reduces mortality without increasing the risk of severe disability. However, as the foundational DHC randomized, controlled trials excluded patients greater than 60 years of age, the appropriateness of DHC in older adults remains controversial. Recent clinical trials among elderly participants, including DESTINY II, reported that DHC reduces mortality, but may leave patients with substantial morbidity. Nationwide analyses have demonstrated generalizability of such data. However, what constitutes an acceptable outcome − the perspective on quality of life after survival with substantial disability − varies between clinicians, patients, and caregivers. Consequently, quality of life measures are being increasingly incorporated into stroke research. This review summarizes the impact of DHC in space-occupying cerebral infarction, and the influence of patient age on postoperative survival, functional capacity, and quality of life-all key factors in the clinical decision process. Ultimately, these data underscore the inherent complexity in balancing scientific evidence, clinical expertise, and patient and family preference when pursuing hemicraniectomy among the elderly.DOI: 10.29245/2572.942X/2017/2.942X/2017/1.1103 View / Download Pdf
Axonal transport is essential for the development, function, and survival of neurons, and impaired axonal transport has been implicated in many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. To date, however, how axonal transport is regulated, and how defective transport leads to neurodegeneration, remain largely unknown. This study by Sato et al. shows that the loss of both JSAP1 and JLP in the cerebellar Purkinje cells (PCs) of mice causes axonal dystrophy followed by gradual, progressive PC degeneration. This study also suggests that JSAP1 and JLP regulate kinesin-1-dependent axonal transport in the brain with functional redundancy, which prevents axonal degeneration and subsequent neuronal death. There is increasing evidence that in neurodegenerative diseases, axonal degeneration precedes neuronal cell death. Thus, elucidating the mechanisms of axonal degeneration may provide promising targets for therapeutic intervention. The JSAP1-null, JLP-null mouse generated in this study may provide a useful animal model for studying the molecular basis of axonal degeneration in neurodegenerative diseases, and for developing therapeutic drugs for these diseases.DOI: 10.29245/2572.942X/2016/8.1095 View / Download Pdf
Michaela F. George, PhD1*, Calliope B. Holingue, MPH1*, Farren B.S. Briggs, PhD, ScM2, Xiaorong Shao, MA1, Kalliope H. Bellesis3, Rachel A. Whitmer, PhD3, Catherine Schaefer, PhD3, Ralph HB Benedict, PhD4, Lisa F. Barcellos, PhD, MPH1,3,51Division of Epidemiology, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, CA, USA
2Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
3Kaiser Permanente Division of Research, Oakland, CA, USA
4Jacobs MS Center, SUNY Buffalo School of Medicine, Buffalo, NY, USA